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Complementary and Alternative Medicine in Diabetes

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June 22, 2011 at 10:23 am

Complementary medicine, also known as complementary and alternative medicine, alternative medicine, functional medicine, and integrative medicine, is re-emerging as one of the fastest growing fields in medicine today. A 1997-1998 national survey showed that 57% of individuals with diabetes reported using complementary and alternative medicine therapies during that year; 35% used complementary and alternative medicine specifically for their diabetes. Individuals with chronic disease often turn to complementary and alternative medicine therapies as adjuncts to standard medical treatment. It is noteworthy, however, that approximately 40% of these patients do not discuss complementary and alternative medicine therapies with their physicians. Of those who do report complementary and alternative medicine use, only 35% of all self-reported supplements are documented in the patient’s chart. Given that several herbs and supplements have properties that augment or attenuate pharmaceutical agents, a knowledge of complementary and alternative medicine treatments for diabetes is imperative.

The list of modalities considered “complementary and alternative medicine” is extensive. Included in this chapter are some of the major therapies of the Naturopathic medical system including lifestyle issues, nutritional supplements, and botanical medicine. Portions of other well-known and well-studied medical systems, such as Ayurveda and Chinese medicine, are included in the botanical section.

A basic tenet of most complementary and alternative medicine medical systems views the individual as a whole: a somatic-psycho-social-emotional-spiritual being. To ignore or minimize these factors and treat simply the disease and its symptoms results in less than optimum care. It is the package of care, rather than the specific modality, that promotes healing and well-being.

Lifestyle

While diet and exercise are lifestyle choices that have obvious impact on diabetes (indeed, in most cases they can hardly be considered complementary and alternative medicine), less apparent dietary topics and practices such as spirituality, social support, stress, and smoking can have profound effects on the disease and on the individual.

Diet

Standard dietary recommendations are well described. However, special mention needs to be made regarding fats and type 2 diabetes. In an extensive review, it was found that quality of fat was essential in glucose metabolism. Polyunsaturated fats and long-chain omega-3 fatty acids were found to be beneficial, while saturated fats and trans fats were detrimental to glucose metabolism and insulin resistance. Indeed, some of the adverse effects of a high fat diet can be ameliorated with omega-3 fatty acids, and an inverse relationship has been shown between vegetable fats and risk of diabetes. It is important that the quality as well as the quantity of fats are addressed, as all fats are not created equal.

Cow’s milk has been implicated in the development of type 1 diabetes. Elevated IgG antibodies to bovine serum albumin were found to average seven times higher in children with diabetes than their healthy counterparts. This, in conjunction with viral exposure, may lead to a cross reaction with the p69 surface cell antigen on beta cells, leading to release of interferon gamma and induction of the beta-cell surface antigen. While these results are controversial, it seems that breast milk should be favored over cow’s milk, at least during the first six months of life.

Smoking

Smoking, while deleterious on many counts, has particular influence on carbohydrate and lipid metabolism. In a group of insulin treated diabetics, smokers had a 15-20% higher insulin requirement and serum triglyceride concentration than their nonsmoking counterparts; this went as high as 30% in heavy smokers. While complete abstinence appears to decrease insulin resistance, smoking cessation methods that employ nicotine (gums, patches) decrease insulin sensitivity. The degree of insulin resistance is correlated to the extent of nicotine used. While encouraging patients to quit smoking is always recommended, care must be taken when prescribing patches and gums to aid this process.

Stress

Acute stress, associated with fight-or-flight response, is accompanied by clear and adaptive severe insulin resistance, quickly reversible with the removal of the stressor. Studies have shown, however, that psychosocial stress may be associated with continued insulin resistance.

Cortisol, a major stress hormone, might contribute to insulin resistance by its tendency to oppose the action of insulin, however, the relationship remains unclear. Evidence suggests that consistently elevated levels of cortisol greatly inhibit nonhepatic glucose utilization.

Social Support

Unlike other disease states, diabetes has a significant impact on the social unit of the patient, in addition to the patient themselves. Diet and exercise, the cornerstones of glucose control, will be affected by the support network of the individual. Change in the habits of people with diabetes will often be intimately tied, for better or worse, to the support of their families, colleagues, and health care systems.

A field test of a one-year program of education and support in Sweden, including ongoing counseling, examined 100 patients with type 2 diabetes. At the study onset, 51% of participants had HbAlc levels at or below 6.5%. After 12 months of education and counseling, 63% had HbAlc levels within this range. Interestingly, participants whose diabetes was diet controlled and rated their loneliness as high were more successful in lowering their HbAlc levels than their non-lonely counterparts. This emphasizes the critical need for social network (i.e., family) education, in conjunction with patient education.

Spirituality

Prayer and religious practice, a cornerstone of illness treatment for millennia, have been largely disregarded in modern medical practice. Recently, however, spirituality has been receiving attention as an adjunct to health care, particularly in the area of immune function. In diabetics, C-reactive protein — an acute inflammatory marker levels are known to be higher than in nondiabetics. C-reactive protein has been tied to cardiovascular disease, a common sequelae of diabetes.

A recent cross-sectional survey of 556 diabetics examined attendance at religious services and C-reactive protein levels. Those who did not regularly attend religious service were more likely to have elevated C-reactive protein than those who attended religious services. After adjusting for demographic variables, health status, smoking, social support, mobility, and BMI, the association between religious attendance and C-reactive protein remained significant for respondents with diabetes.

Conclusions

The psychosocial-emotional factors in diabetes can and should be addressed in caring for the individual. While maintenance of glycemic control is the ultimate goal, the well-being and quality of life of the patient must be addressed as well.

Nutritional supplements

Several nutritional components have an effect on insulin resistance and diabetic control. Further, diet, along with medications, may affect micronutrient status in diabetic populations, leading to complications in their glucose control and in general health. Common vitamins, minerals, and nutrients that affect diabetes are discussed, as well as nutrient status affected by diabetes medications.

Vitamins

Minerals

Nutrients

Botanical Medicine

Conclusions

It should be emphasized that while some of the most common modalities of complementary and alternative medicine are presented, Naturopathic medicine, similar to Native American, Ayurvedic, or Chinese medical systems, does not operate solely by treating the disease. Instead, the emphasis is on treating the whole person. An individual with diabetes, for example, would likely receive some of the treatments outlined in this chapter. However, treatment would be individualized to that particular person, and other modalities such as homeopathy, counseling, acupuncture, bodywork (manipulation, hydrotherapy), and/or energy work (Reiki or another healing touch therapy) would be applied as well. It is precisely this individualization of treatment that make complementary and alternative medicine medical systems so difficult to study in the reductionistic paradigm that guides current medical thinking. With time and understanding, however, medical systems rather than single treatments are beginning to be examined; it is hoped that this will continue in the future.

TABLE. Less Well-Studied Botanicals that May Benefit Diabetes

Herb Effects
Aloe vera FBS and triglycerides in type 2 with or without standard anti-diabetic agents; hypoglycemic effects in type 2 and animal models; decreased FBS and HbAlcin type 2
Salt bush (Atriplex halimu) Improved blood glucose regulation and glucose tolerance in type 2; prevents diabetes in sand rats
Konjac (Amophophallus Konjac C. koch) Reduced plasma cholesterol, LDL, total: LDL ratio, fasting glucose in type 2 on oral hypoglycemics
Cinnamon

(Cinnamomum cassia)

Decrease serum glucose, triglycerides, cholesterol, LDL in type 2
Ivy gourd (Coccinia indica) Change in glycemic control better than conventional drug in type 2; blood glucose lowering in animals
Horsetail (Equisetum myriochaetum) Decreased blood glucose, no change in insulin following OGTT in type 2
Fig leaf (Ficus carica) Decrease in postprandial glucose and insulin requirement in type 1; short- and long-term hypoglycemic effects in animals
Ginkgo biloba Improves blood flow, thereby | sequelae of diabetes
Holy basil (Ocimum sanctum) Positive effects on fasting and postprandial glucose in type 2; hypoglycemic effects in animal models
Nopal (Opuntia streptacantha) Decreased fasting glucose and insulin levels in type 2; decrease postprandial glucose and HbAlc with synergistic effects with insulin in animal models
Oolong tea Decreased concentration of plasma glucose and fructosamine in type 2 or hypoglycemics
Psyllium (Plantago ovata) Total cholesterol, | LDL, | postprandial glucose rise
Pterocarpus marsupium Prevents beta-cell damage in rats; regenerates functional pancreatic bets-cells in animals
Milk thistle (Silibum marianum) Improved glycemic control in cirrhotic type 2 patients
Zygophyllum gaetulum Short- and long-term reduction in blood glucose, normoglycemia without change in body weight in type 2

 

 

 

Vitamins

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June 22, 2011 at 10:22 am

Vitamins are vital for life, and, ideally, should be maintained in adequate levels in the foods we eat. With over-farming and genetic modification of foods, the vitamin and mineral content today may not supply the nutrients of the foods past, or even meet what is necessary for optimal health. Add in fast foods, convenience foods, and high fat and sugar choices (some very cleverly disguised), and the ability to meet nutritional requirements becomes questionable.

A large longitudinal study found that adults who used vitamin supplements were 24% less likely to develop diabetes than those who did not. The protective effect of vitamins remained when adjusted for age, race or ethnicity, education, cigarette smoking, systolic blood pressure, use of antihypertensive medication, serum cholesterol, body mass index, exercise, alcohol consumption, fruit and vegetable intake, percent calories from fat, and total energy intake. Clearly, vitamins are an important part of health maintenance.

Vitamin B3 (Niacin, Niacinamide, Nicotinamide)

Niacin plays an important role in fat, cholesterol, and carbohydrate metabolism. It is an essential component of the glucose-tolerance factor, giving it a key role in hypoglycemia and diabetes. Niacin has been shown to be deficient in people with diabetes.

Niacinamide, a water-soluble amide of nicotinic acid, has been used successfully to prevent or delay the onset of type 1 diabetes, lowering the incidence from 15-20 per 100,000/year to 8 per 100,000/year. Treatment with high-dose niacinamide appears to delay rather than completely reverse disease development in those with preexisting type 1 diabetes. However, treatment of ‘at risk’ groups, in the majority of studies, shows promise in disease prevention.

Lipid profiles in people with diabetes have been improved with niacin supplementation. Niacin has been shown to increase HDL, decrease triglycerides, and decrease LDL in patients with or without diabetes. HbAlc levels remained unchanged in this study, however, another study found extended release niacin improved both HbAlc and lipid profile in diabetics.

Self-medication of high-dose niacin should be discouraged. Flushing, stomach irritation, and hepatic damage may occur with high doses. In normal individuals, niacin has been known to cause insulin resistance. Because of the capacity to disrupt blood sugar control, diabetics taking any form of niacin must monitor their glucose closely.

Vitamin B6 (Pyroxidine), Bn (Cobalamin), and Folk Acid (Folate)

Vitamins B6 and Bi2 have been shown to be deficient in people with diabetes, especially those with diabetic neuropathy. Further, B12 absorption is reduced by metformin. B6 prevents the glycosylation of proteins, and may be a safe treatment for gestational diabetes. Studies have shown that folate, B6, and Bi2 reduce homocysteine levels in diabetics.

Biotin

Biotin supplementation has been shown to enhance insulin sensitivity and increase the activity of glucokinase. Biotin significantly lowers fasting blood sugar and improves glucose control in both type 1 and type 2 diabetes. Insulin requirements must be monitored with high-dose biotin supplementation.

Vitamin C (Ascorbic Acid)

Because the transport of vitamin C into cells is facilitated by insulin, it is often deficient in people with diabetes. High doses of vitamin C have been found to inhibit aldose reductase, inhibiting the conversion of D-glucose to d-sorbitol, then to fructose. Left unchecked, sorbitol and fructose accumulate in cells, causing damage to glucose insensitive tissues: the eye lens, renal glomeruli, and peripheral nerves, exacerbating many of the common complications of diabetes.

Vitamin E

Vitamin E appears to play a significant role in preventing diabetes. In a 4-year prospective study, a low plasma vitamin E was associated with a 3.9-fold increase in risk of diabetes. A 1 µmol/l decrement in serum vitamin E corresponded with a 22% increment in diabetes risk. Supplementation of vitamin E not only improves the action of insulin, but also has a number of beneficial effects that may prevent long-term complications of diabetes.

Minerals

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June 22, 2011 at 10:21 am

Like vitamins, minerals are essential to life, and theoretically should be available from foods. Since most multivitamins also contain minerals, it may be presumed that the decrease in diabetic incidence and complications seen with vitamin supplementation may include minerals as well. Several specific minerals, however, bear further mention.

Chromium

Trivalent chromium (Cr3) is a key constituent of glucose-tolerance factor, and deficiency has been linked to decreased glucose tolerance, increased serum insulin levels, and decreased number of insulin receptors. There is evidence that marginal chromium deficiency is common in the United States.

Chromium is a part of a glucose/insulin system that maintains homeostatic control of blood glucose. Cr3 has also been shown to have a positive influence on individuals with no diabetic symptoms. Serum chromium levels in healthy individuals were found to be inversely related to insulin peaks in response to a glucose challenge. In people with diabetes, however, levels did not fluctuate with respect to insulin.

Chromium deficiency has been associated with hyperglycemia in test animals as well as humans, and is reversible by supplementation. It is effective in treating various types of diabetes, including type 1 and 2, gestational, and steroid-induced. Treatment of type 2 diabetes with Cr3 has led to improvement in blood glucose, insulin, and HbAlc levels in a dose-dependent manner. Higher Cr3 doses also resulted in a decrease in cholesterol levels.

While many studies show positive effects with chromium supplementation, the results are mixed. Further, some concern exists regarding high doses and renal dysfunction, including decreased thirst, fatigue, and urinary frequency. Other studies did not replicate this finding at the same dose; no changes in renal or hepatic function were found by laboratory testing. The Drug-Induced Nutrient Depletion Handbook states that side effects and toxicity with chromium supplementation are virtually nonexistent in humans.

Diets high in simple sugars increase urinary excretion of chromium, but show no change in absorption rates. Antacids have been found to decrease absorption.

Magnesium

Hypomagnesemia is common in diabetes. Deficiency can potentially cause states of insulin resistance, and supplementation may prevent some of the complications of diabetes such as retinopathy and heart disease.

Magnesium levels are related to insulin resistance in type 1 and type 2 diabetes, as well as nondiabetics. Between 25% and 48% of type 2 diabetics have been shown to have low magnesium levels.

The research on magnesium supplementation and glycemic control is mixed. Two trials showed a decrease in fasting plasma glucose and an increase in postprandial insulin. Three other trials did not show a change in blood glucose or HbAlc level. However, magnesium deficiency in people with diabetes is not under dispute. Given that magnesium toxicity is rare, it would seem wise to consider supplementation. Caution should be used, as high doses may cause diarrhea.

Potassium

A high potassium diet has several positive results for diabetes control: it yields improved insulin sensitivity, responsiveness, and secretion; it replaces potassium lost by exogenous insulin administration; and it reduces the risk of heart disease, atherosclerosis, and cancer. A potassium-depleted diet was found to lead to insulin resistance at postreceptor sites, reversible when potassium was resupplied.

Diet is the preferred method of increasing potassium intake, as supplementation with potassium salts can cause nausea, vomiting, diarrhea, and ulcers. Further, kidney disease can result from potassium toxicity in people with diabetes, so supplementation other than dietary should be used with care.

Vanadium (Vanadyl Sulfate)

Vanadium is a trace mineral believed to regulate fasting blood sugar and improve sensitivity to insulin. It is thought to be insulin-mimetic, and upregulate insulin receptors.

In three small studies, vanadium has been shown to decrease fasting blood sugar in people with diabetes; two of these also reported improvement in HbAlc and insulin sensitivity. Beneficial effects remained after cessation of active treatment. No change in insulin sensitivity was found with supplementation in obese nondiabetics.

Gastrointestinal discomfort was reported by many subjects, however, organically chelated vanadium compounds cause less irritation than vanadium salts.

Zinc

Zinc is involved with the synthesis, secretion, and utilization of insulin. It also exerts a protective effect against beta-cell destruction. People with diabetes are prone to insulin depletion due to excess excretion, and zinc supplementation has been shown to improve insulin levels in both type 1 and type 2 diabetes.

 

Nutrients

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June 22, 2011 at 10:20 am

There are several nutritional components beyond vitamins and minerals that either have an affect, or are affected by diabetes. Further, oral hypoglycemics and insulin may deplete some of these essential nutrients, warranting supplementation.

Essential Fatty Acids

Essential fatty acids , including omega-3 (n-3), omega-6 gamma linoleic acid, eicosapentaenoic acid, and do-cocsahexaenoic acid have been studied extensively for their beneficial effects on cholesterol, triglycerides, blood pressure and cardiovascular disease, autoimmune disease, and inflammation. Several compounds have been shown to be particularly relevant to diabetes, beyond their cardiovascular protective effects.

Diabetes, both human and experimental, has been associated with disturbances in Essential fatty acids metabolism; in particular, the conversion of linoleic acid to gamma linoleic acid is inhibited. Linoleic acid shares functional similarities to potent insulin sensitizers, and has been shown to normalize impaired glucose tolerance and improved hyperinsulinemia in animal studies. Gamma linoleic acid, however, is an important component of diabetic complications, particularly neuropathy. In a large multicenter trial, gamma linoleic acid supplementation was provided in the form of evening primrose oil to patients with diabetic neuropathy. Following 1 year of treatment, all symptoms of neuropathy improved. Sources of gamma linoleic acid include evening primrose oil, borage oil, and black currant oil.

Fish oils are an important source of long-chain n-3 fatty acids, eicosapentaenoic acid, and do-cocsahexaenoic acid. The ability of fish oil to enhance the rate of glycogen storage allows skeletal muscle to increase its uptake of glucose, even under conditions where fatty acid oxidation is accelerated. Fish oil enhances insulin secretion by incorporation of n-3 fatty acids into the plasma membrane. This reduces the concentration of amino acids in the plasma membrane, decreasing the production of prostaglandin 2 (PGE2) which, in turn, suppresses the production of cAMP, a well-known enhancer of glucose-induced insulin secretion. Consequently, fish oil enhances insulin secretion from beta cells, regulating blood sugar.

Fish oils have biological properties of potential relevance for the prevention of type 1 diabetes. One large case control study found that cod liver oil, given in the first year of life, was associated with significantly lower risk of type 1 diabetes.

In type 2 diabetes, studies have shown mixed results. One study examined established type 2 diabetics, providing a diabetic diet along with eicosapentaenoic acid and do-cocsahexaenoic acid supplements, or diet alone. Essential fatty acids supplementation resulted in significantly greater improvement in glycemic status, blood pressure, and lipid profiles, as well as reduction in measures of oxidative stress. In other studies, supplementation with fish oils resulted in no change in either fasting serum insulin levels or insulin sensitivity, and one study found an increase in fasting blood glucose following fish oil intervention. However, given the proven vascular benefits of EFAs, with careful monitoring supplementation may be indicated.

Medium chain triglycerides are a component of many foods, with coconut and palm oils being the dietary sources with the highest concentrations. In an inpatient setting, an experimental diet containing 78% of fat calories as Medium chain triglycerides (31% of total energy intake) increased glucose metabolism in patients with type 2 diabetes. In five outpatients with type 2 diabetes, an experimental diet containing 18% of calories from Medium chain triglycerides led to a slight reduction in postprandial blood sugar and no effect on fasting blood sugar. While promising, the role of Medium chain triglycerides in the management of diabetes remains to be decided.

Blood lipid levels should be monitored when supplementing with EFAs. While the results are mixed, and several studies have shown improved lipid levels, but one study found an increase in cholesterol when supplementing people with type 1 diabetes with n-3 fatty acids.

Alpha Lipoic Acid (Thioctic Acid)

Alpha lipoic acid is a naturally occurring thiol, synthesized in the liver. It is a potent antioxidant, a cofactor in many enzymatic complexes, and may play a role in glucose oxidation. Alpha lipoic acid has been shown to improve insulin resistance in a number of animal models, and experimental trials have indicated usefulness in insulin resistance, when delivered both parenterally and orally.

Insulin sensitivity and glucose effectiveness following oral glucose-tolerance test was performed on lean and obese people with type 2 diabetes. Alpha lipoic acid treatment was associated with increased glucose effectiveness in both lean and obese groups, while higher insulin sensitivity and lower fasting glucose were significantly changed in lean subjects only. In another study, blood glucose levels following Alpha lipoic acid supplementation were not changed, however changes in coagulation factors and marked lipid lowering were seen.

A dosage study of Alpha lipoic acid showed a mean increase of 21% in insulin-stimulated glucose disposal in treated subjects, with no significant differences between dosage levels. A relatively low dose, therefore, is sufficient to produce effects.

Coenzyme Qho (Ubiquinone)

Coenzyme Cho (CoQio) is a cofactor in the mitochondrial electron transport chain. Because an adequate supply of energy is essential for the health of virtually all human tissues, CoQio is a vital nutrient. Many recent studies have demonstrated the effectiveness of CoQio in maintaining cardiovascular health.

Several studies have explored the role of CoQio in diabetes. Administration of C0Q7 (a nutritionally equivalent analog of C0Q10) resulted in fasting blood sugar level declines of at least 30% in 31% of the patients. A second study showed improvement in pain and paresthesias in diabetic neuropathy. Several negative studies, however, have indicated that beneficial effects of C0Q10 administration may not be apparent in the short term.

Many of the oral hypoglycemics and all of the lipid-lowering statins deplete C0Q10. Given its known beneficial cardiovascular effects, and emerging effects on glucose control, supplementation in people with diabetes should be considered.

TABLE . Oral Hypoglycemics, Exogenous Insulin, and Nutrient Depletion

Hypoglycemic agent Nutrient depleted Potential effects
Acarbose (Precose) Coenzyme Qio Congestive heart failure, high blood pressure, angina,

mitral valve prolapse, stroke, cardiac arrhythmias,

cardiomyopathy, lack of energy, gingivitis, weakened

immune system

Acetohexamide (Dymelor)
Glimepride (Amaryl)
Glipizide (Glucotrol)
Glyburide (Micronase)
Tolazamide (Tolinase)
Metformin (Glucophage) Folic acid Homocysteine, megaloblastic anemia, headache,

fatigue, hair loss, anorexia, insomnia, nausea, diarrhea, f infections

  B12 Fatigue, peripheral neuropathy, macrocytic anemia, confusion, depression, memory loss, poor blood clotting, dermatitis, anorexia, nausea, vomiting
Insulin K+ Cardiac arrhythmias, poor reflexes, weakness, fatigue, thirst, edema, constipation, dizziness, mental confusion, nervous disorders

Conclusion

This list of nutritional supplements is not meant to be exhaustive. Several other substances, including beta carotene, calcium, manganese, L-carnitine, and glutathione, have shown promise in the treatment of diabetes.

The standard medications for glycemic control can and do influence nutritional status. Table  Oral Hypoglycemics, Exogenous Insulin, and Nutrient Depletion presents the most commonly prescribed diabetes medications, their effect on nutritional substances, and the potential consequences.

Botanical Medicine

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June 22, 2011 at 10:17 am

There are literally thousands of herbal compounds available and beneficial for various health conditions. Most of the herbs described in this section have been used for centuries, and are just now beginning to be considered in mainstream medicine as options for diabetic control. As testing of botanicals increase, more use of the ancient treatments may be seen.

This section, like the nutritional supplements, cannot be considered exhaustive. The most rigorously studied herbs with the longest and most effective history of use are discussed, with contraindications and interactions presented in tabular form. A table with less well-studied, yet promising, treatments follows.

Bitter Melon (Momordica charantia)

Bitter melon is indigenous to tropical areas in Asia, India, South America, and Africa. It has been used widely in folk medicine as a treatment for diabetes. Theoretical mechanisms of action include increased insulin secretion, tissue glucose uptake, liver muscle glycogen synthesis, glucose oxidation, and decreased hepatic gluconeogenesis. The blood sugar lowering capabilities have been clearly established in clinical trials and experimental models.

Charantin, an active component of bitter melon, is a more potent hypoglycemic agent than tolbutamide, a first generation sulfonylurea. It also contains an insulin-like polypeptide, structurally and pharmacologically comparable to bovine insulin, which lowers blood sugar levels with fewer side effects than exogenous insulin injections.

Positive effects have been shown using bitter melon. One study showed 73% of people with type 2 diabetes had improved glucose tolerance with bitter melon juice. Another small study showed a 54% decrease in postprandial blood sugar and a 17% reduction in glycosylated hemoglobin with an aqueous extract. No adverse effects have been reported in human studies.

Bitter melon may have additive effects when taken with other glucose-lowering agents. While capsules are available, the juice or extract form has been used in most studies. However, as the name implies, the juice is extremely bitter and may be difficult to make palatable.

Bilberry (Vaccinium myrtillus)

Leaves of the bilberry plant were widely used for diabetic treatment before the availability of insulin. In addition, the berries, containing anthocyanidins, have beneficial effects on microvascular abnormalities common in diabetes.

Bilberry has been shown to lower plasma glucose and triglycerides in animals. In humans, it has been shown to improve retinopathy and normalization of collagen deposition. Interestingly, a recent study of mulberry, another rich source of anthocyanidins, compared it to the standard antidiabetic medication glibenclamide. Patients with mulberry therapy significantly improved their glycemic control over those on glibenclamide treatment. Mulberry also significantly decreased serum total cholesterol (12%), triglycerides (16%), plasma free fatty acids (12%), LDL (23%), VLDL (17%), plasma peroxides (25%), and urinary peroxides (55%), while increasing HDL by 18%. Glibenclamide showed moderate improvement in glycemic control, but only had a significant effect on triglycerides (10%), and peroxides (15% plasma, 19% urine). Neither treatment affected HbAlc levels.

No side effects or contraindications are known with bilberry fruit. High doses and prolonged use of the leaves, however, may lead to chronic intoxication. This manifested in animals as cachexia, anemia, icterus, and excitation. Extremely high doses (1.5 g/kg per day) of the leaves over long periods could result in death.

Fenugreek (Trigonella foenum-graecum)

Fenugreek is one of the oldest medicinal plants. Proposed mechanisms of action include delay of gastric emptying, slowing carbohydrate absorption, inhibition of glucose transport, increased erythrocyte insulin receptors, and modulation of peripheral glucose utilization. In animal and several small human trials, fenugreek seeds have been found to lower fasting serum glucose levels, both acutely and chronically.

In people with type 1 diabetes, ingestion of defatted fenugreek seed resulted in significant improvement in fasting blood sugar levels and glucose tolerance, as well as a 54% reduction in 24-hour urinary glucose excretion, and reductions in LDL, VLDL, and triglycerides, indicating that fenugreek may aid with insulin secretion.

Several small clinical trials have been conducted in type 2 diabetics. In one study, fenugreek-treated patients showed statistically significant mean improvements for glucose-tolerance test scores and serum-clearance rates of glucose. In a series of two crossover studies, significant mean improvements were seen in the fasting blood glucose levels and glucose-tolerance test results in the fenugreek-treated patients, even though the dose of their standard antidiabetic medication (glibenclamide, glipizide, or metformin) was reduced by 20% prior to the study period. The fenugreek patients also reported subjective improvements in polydipsia and polyuria. In a study of newly diagnosed people with type 2 diabetes, however, the benefit of fenugreek seeds was not seen to be significantly different than diet and exercise.

In their review of clinical trials, Yeh and colleagues found that whole raw seeds, extracted seed powder, gum isolate of seeds, and cooked whole seeds seemed to decrease postprandial glucose levels, while degummed seeds and cooked leaves did not.

No adverse effects have been reported in clinical trials of fenugreek, but interactions are possible due to decreased intestinal absorption. Hypoglycemic symptoms are to be expected, and should be monitored.

Garlic and Onion (Allium sativa and Allium cepa)

Onions and garlic have demonstrated blood sugar lowering action in several studies. The active constituents are believed to be the sulfur containing compounds allyl propyl disulfide (APDS) and diallyl disulfide oxide (allicin). APDS may lower glucose levels by competing with insulin for inactivating sites in the liver, resulting in an increase of free insulin.

In clinical trial, onion extracts reduced blood sugar levels in a dose dependent manner. A second small study showed acute decrease in fasting blood glucose and increase in insulin, showing an insulin-mediating effect in nondiabetics. Also in nondiabetics, using garlic was shown to decrease fasting serum glucose. Studies in diabetics, however, have been mixed.

As well as potential hypoglycemic effects, garlic and onions have cardiovascular and immune enhancing qualities, and are generally well tolerated. The use of these herbs in diabetes is valuable. Care is indicated with patients on anticoagulants.

Ginseng Species (Panax ginseng and Panax quinquefolius)

Ginseng root has been used for over 2,000 years for health promotion. Of the ginseng species, American ginseng (P. quinquefolius) and Asian ginseng (P. ginseng) are the most commonly used. Reported mechanisms of action include decreased rate of carbohydrate absorption into the portal hepatic circulation, increased glucose transport, and uptake mediated by nitric oxide, increased glycogen storage, and modulation of insulin secretion.

There are several clinical trials that provide evidence for the hypoglycemic effects of ginseng. One study demonstrated a reduction in the levels of fasting blood glucose and HbAlc in type 2 diabetes when ginseng was taken before meals. The subjects also showed mood elevation, improved psychophysiological performance and physical activity, and reduced body weight.

In a second group of studies on ginseng and people with type 2 diabetes, ground American ginseng root in capsules of varying dosage were administered prior to an oral glucose challenge. Ginseng significantly affected postprandial glycemia, with significant interaction for area under the curve. Compared with placebo, all ginseng doses reduced glycemia, without significant effect as to time of administration. In a second similar study, people without diabetes were compared to those with type 2 diabetes. In nondiabetics, significant reductions in postprandial glucose were found only when the ginseng was taken 40 minutes prior to the challenge. In people with diabetes, however, reductions in glucose were seen regardless of when ginseng was taken, either at challenge or before .

Adverse effects for ginseng have been reported, and include nervousness and excitation. These generally diminish with increased use or dosage reduction. Ginseng may inhibit the effects of warfarin, and interact with the monoamine oxidase inhibitor phenelzine. Massive doses of ginseng may result in “ginseng abuse syndrome,” characterized by hypertension, insomnia, hypertonia, and edema.

Gymnema (Gymnema sylvestre, Gumar)

Gymnema, an Ayurvedic herb, has been used for centuries as a treatment for diabetes. Gumar, the Hindi name, literally means “destroyer of sugar.” Mechanism of action is unknown, but postulations include an increase in glucose uptake and utilization, increase in insulin release through cell permeability, increase in beta-cell number, and stimulation of beta-cell function.

Chewing gymnema blocks the sensation of sweetness. Individuals who had gymnema extracts applied to their tongues prior to meals ate fewer calories compared to controls. This has not been shown with ingestion of capsules or tablets, however.

In people with type 1 diabetes, supplementation with gymnema resulted in insulin requirements being decreased by one half, and reduced average blood glucose levels. HbAlc levels were reduced, but still remained higher than normal. Cholesterol and triglycerides were lowered significantly. Gymnema appears to enhance the action of insulin in type 1 diabetes.

In a study of 22 people with type 2 diabetes, gymnema taken along with their oral hypoglycemic drugs improved glucose control in all 22 participants. Further, 21 of the 22 were able to reduce their oral hypoglycemic medication dose considerably, and five were able to discontinue medication altogether and maintain glycemic control with gymnema alone.

Gymnema extract given to healthy volunteers does not produce any blood sugar lowering or hypoglycemic effects. No side effects have been noted.

Soy (Phytoestrogens)

Phytoestrogens in general, and soy in particular, have been receiving increased attention of late due to substantial data that consumption of plant-based phytoestrogens have a beneficial impact on health. In diabetes, soy is thought to be beneficial both for glycemic control and for obesity, although the mechanism of action remains unclear.

In a recent study of postmenopausal women with diet-controlled type 2 diabetes, phytoestrogen supplementation resulted in significantly lower mean values for fasting insulin, insulin resistance, HbAlc, total cholesterol, LDL, cholesterol/HDL ratio, and free thyroxine. These results show that dietary supplementation with soy phytoestrogens favorably alter insulin resistance, glycemic control, and serum lipoproteins. A study examining a soybean-derived Touchi extract was tested against placebo in people with borderline type 2 diabetes. Initial fasting glucose and HbAlc gradually decreased, reaching statistical significance after 3 months. There were no complaints of side effects or abdominal distention.

A review of the literature on soy and diabetes revealed that soy protein, along with soy fiber, decreased LDL, VLDL, total cholesterol, and triglycerides; decreased postprandial hyperglycemia with no effect on serum insulin; and improved glucose tolerance and glycated hemoglobin. While the number of studies is small, the results are promising.

TABLE. Interactions and Contraindications of Selected Herbs

Herb Contraindications Interactions
Bitter melon (Momordica charantia) Pregnancy Insulin, chlorpropamide
Bilberry (Vaccinium myrtillus) None known Warfarin and antiplatelet drugs
Fenugreek (Trigonella foenum-graecum) Pregnancy Insulin, cholesterol lowering drugs, may retard absorption of oral drugs, may interfere with warfarin
Garlic and onion (Allium sativa and Allium cepa) Stomach inflammation, pregnancy, low thyroid, presurgery, acid reflux Insulin, warfarin, indomethacin, dypiridamole, anticoagulants, may be protective against acetaminophen and isoprenaline toxicity
Ginseng species (Panax ginseng and P. quinquefolius) Hypertension, acute asthma, acute infection, excessive menstruation, nosebleeds Insulin, warfarin, caffeine, phenelzine, lithium, amitriptyline, potentiates amoxicillin and clavulanic acid, morphine, methamphetamine
Gymnema (Gymnema sylvestre, Gumar) None known Insulin, enhances glybenclamide and tolbutamide
Soy (Phytoestrogens) Nontoxic goiter Thyroxine in infants, estrogen replacement therapy

Drug-Herb Interactions

While generally well tolerated, many botanical substances react with other medications. Table presents the contraindications and interactions of the botanicals discussed.

Less Well-Studied Beneficial Herbs

Table Less Well-Studied Botanicals that May Benefit Diabetes

provides botanical species that are not as well studied for their effects on diabetes, but have shown potential in at least one study.

Conclusion

A plethora of botanical substances exist that affect diabetes. Many of the lesser known herbs presented are from the Ayurvedic or Chinese medical systems, and have been used successfully in other countries with good results, but without the benefit of the rigorous scientific study required in the United States. As the world becomes smaller, more of these traditional medicines may become available.

 

Phytotherapy in the Treatment of Benign Prostatic Hyperplasia

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June 21, 2011 at 9:48 am

The use of plants or plant extracts for a variety of medicinal purposes (phytotherapy), including the treatment of voiding disorders, dates from ancient times. There is currently wide variation in the use of phytotherapeutic agents in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia in different parts of the world. In some European countries, for example France and Germany, plant extracts are among the most commonly recommended initial treatment options in men with voiding symptoms. These agents are available by prescription in many cases and patients may be reimbursed for their cost by health ministries or insurance companies. Although many Americans use phytotherapeutic products, few physicians in the United States recommend such therapy for men with benign prostatic hyperplasia, and all costs associated with such treatment are borne by the patient. Despite the lack of reimbursement by third-party payers for medicinal botanicals, it is estimated that $500 million to $1 billion is spent annually in the United States for such products. While it is widely perceived by many patients that it is advantageous to treat a variety of chronic medical conditions, such as lower urinary tract symptoms, with “natural” remedies, there is limited scientific evidence to support the use of these agents in most cases.

Phytotherapeutic agents used for treating men with lower urinary tract symptoms have not generally been subjected to the same rigorous testing standards as other more commonly accepted therapies, such as alpha-blockers and 5 a-reductase inhibitors. This situation has changed somewhat in recent years as several European companies that market phytotherapeutic products have responded to this criticism and sponsored multicenter clinical trials. In contrast, medicinal botanicals are generally categorized as food additives in the United States and are therefore not eligible for patent protection. This is a significant financial disincentive for American companies to support clinical research into these products. In addition, most European companies have elected not to pursue approval of their phytotherapeutic products in the United States due to a variety of economic and other factors.

Most medicinal botanicals contain multiple chemical components and it is generally unclear which, if any, of these ingredients are responsible for clinical activity.

There is also a lack of standardization of phytotherapeutic agents in the United States, potentially leading to marked variability in the chemical composition of natural products sold by different companies. Saw palmetto, the most popular plant extract used for treating lower urinary tract symptoms, is sold in one form or another by 30 or more companies in the United States. In some cases, these products include saw palmetto alone while others contain a mixture of herbal products, vitamins, and minerals. In Europe, saw palmetto is most commonly marketed as a prescribable agent (Permixon), which is manufactured in France. Permixon is the most extensively studied form of saw palmetto but it is not clear that similar results reported with this specific agent will be seen with other forms of saw palmetto available in the United States. Most patients are not aware of the vast potential differences that may exist between the chemical composition and efficacy of products with similar or identical names.

Proposed Mechanisms of Action of Phytotherapeutic Agents

There have been a wide variety of plant extracts recommended for patients with lower urinary tract symptoms and benign prostatic hyperplasia. The most common components of these agents include phytosterols, fatty acids, terpenoids, and plant oils. The improvement in voiding symptoms and benign prostatic hyperplasia are most often attributed to phytosterols, a class of compounds related to cholesterol. Beta-sitosterol is felt to be the most important phytosterol, and a variety of forms are present in most plant extracts used for treating benign prostatic hyperplasia.

There have been a number of suggested mechanisms of action associated with phytosterols, including antiandrogenic effects, direct inhibition of prostatic growth, and anti-inflammatory effects, These actions have been most commonly demonstrated using in vitro studies and experimental models in which supra-physiologic doses are frequently utilized. While these studies may suggest important mechanisms, it is difficult to assess the clinical relevance of these actions in some cases. The most important example of this discrepancy concerns the evidence that saw palmetto acts as a 5 a-reductase inhibitor. Although this action has been demonstrated in a variety of in vitro studies, clinical studies performed among men receiving saw palmetto have generally failed to show significant enzyme inhibition (based on changes in prostate size and serum prostate-specific antigen levels). In addition to concerns regarding mechanisms of phytotherapeutic agents, there is limited available information concerning bioavailability, and some plant extracts have been shown to be poorly absorbed from the gastrointestinal tract. Finally, in many cases scant information regarding pharmacodynamics is available.

Saw Palmetto

Pygeum africanum

Phytosterols

Pollen Extract

Mepartricin

Although Mepartricin is not truly a plant extract, it is best grouped with other phytotherapeutic agents used for treating symptomatic benign prostatic hyperplasia. Mepartricin is a semisynthetic polyene derived from a Streptomyces strain. It appears to have favorable effects in men with benign prostatic hyperplasia by selective binding activity with estrogens. This agent is produced in Italy and is marketed under the trade name Ipertrofan. Mepartricin binds to estrogen in the intestine, thus inhibiting its reabsorption. Since most estrogens are reabsorbed in the intestine after excretion into the bile, a decrease in reabsorption leads to a reduction in circulating serum levels. This leads to a decline in estrogen-induced stimulation of prostatic growth. In animal experiments, Mepartricin has been demonstrated to increase fecal excretion of estrogen and reduce blood and prostate estrogen concentrations as well as estrogen receptor levels within the ventral prostatic lobes. In patients with benign prostatic hyperplasia, treatment with Mepartricin has led to a significant decrease in the serum concentration of estrone, estradiol, and estriol.

In a multicenter trial conducted in several European countries, 198 men with untreated symptoms secondary to benign prostatic hyperplasia with an IPSS of 12 to 24 were randomized to receive Mepartricin or placebo for 24 weeks. Patients also were required to have a peak urinary flow rate of 6 to 15 cc per second to be enrolled in the study. The patients treated with Mepartricin had a significantly greater reduction in symptom score and increase in urinary flow rate compared to controls as well as an improved quality-of-life measure. No significant differences were seen in the two groups with regard to changes in prostate size, prostate-specific antigen level, or postvoid residual urine volume. No serious adverse events were noted among men in either group. Mepartricin appears to be a promising treatment option, with a unique mechanism of action, for men with symptomatic benign prostatic hyperplasia. Further study of this agent is planned.

Other Plant Extracts

In addition to the phytotherapeutic agents discussed above, a variety of other plant extracts have been investigated in men with symptomatic benign prostatic hyperplasia. Bazoton is the trade name of an extract from the plant Radix urticae and has a steroid-glycoside composition. This product has been tested in Hungary and appears to be an inhibitor of intra-cellular sex hormone-binding globulin receptors. In a limited, nonrandomized study, treatment with Bazoton led to symptomatic improvement as well as improvements in urinary flow rate and postvoid residual volume.

In Germany, extracts from the roots of Urtica dioica (stinging nettles) are widely used for treating men with benign prostatic hyperplasia. The suggested mechanisms of nettles include suppression of prostatic cell growth and metabolism, inhibition of a variety of prostatic growth factor interactions, and blockage of the attachment of sex hormone-binding globulins to prostatic membrane receptors. Although randomized, placebo-controlled trials demonstrating subjective and objective benefit using nettles have been reported in Germany, these studies have generally included small numbers of patients treated for intervals of only 1 to 3 months. The value of stinging nettles in men with benign prostatic hyperplasia therefore remains unclear.

Other studies have investigated combination products incorporating two or more phytotherapeutic agents that have been used in men with benign prostatic hyperplasia.’ These trials have frequently demonstrated subjective and objective benefit in treated patients compared to controls. The value of these studies, however, has generally been limited by small numbers of patients and short treatment intervals.

Finally, therapeutic benefit has been suggested for other plant extracts such as those from pumpkin seeds, unicorn root, and rye pollen. No recognized studies using these agents in men with benign prostatic hyperplasia have been presented to date.

Summary

There is growing interest in the United States in the use of “natural remedies” to treat patients with chronic medical conditions such as benign prostatic hyperplasia. Most American physicians have limited knowledge concerning these treatments and are unable to advise patients regarding their use. Due to the proliferation of health food and vitamin stores, the growing popularity of the Internet, and aggressive direct marketing to consumers, there has been a significant increase in the overall use of medicinal botanicals. Unlike therapies such as alpha-blockers and 5 a-reductase inhibitors, there have been few properly conducted trials of plant extracts in men with benign prostatic hyperplasia. One of the primary reasons for the lack of scientific study of these agents is the absence of significant financial incentive for American companies marketing phytotherapeutic products to support such research, given that such products are generally not eligible for patent protection.

Additional difficulties in assessing the efficacy of plant extracts in men with benign prostatic hyperplasia include the lack of standardization of these agents. Vast differences are likely to exist between similar products sold by different manufacturers. This issue is further confused by the widespread availability of combination products that often contain vitamins and minerals as well as a variety of plant extracts. There is a clear need for randomized, controlled trials of phytotherapeutic products in men with benign prostatic hyperplasia to ascertain the true value of these agents.

Saw Palmetto

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June 21, 2011 at 9:47 am

The most popular plant extract used for treating lower urinary tract symptoms is derived from the berry of the American dwarf palm tree (saw palmetto [Serenoa repens]), which is found in Florida and other areas of the southeastern United States. As described above, saw palmetto is sold under a variety of trade names in the United States and Europe. Permixon, the most extensively studied form of saw palmetto, is a liposterolic extract of the berry that contains a complex mixture of free fatty acids, phytosterols, and other compounds and is available in parts of Europe. In animal studies, some components of Permixon have been demonstrated to accumulate in normal and hyperplastic prostatic cells. In addition, bioavailability studies in humans have shown that at least some of the compounds contained in Permixon are absorbed through the intestinal tract.

Mechanisms of Action

Many mechanisms of action of saw palmetto have been proposed, including anti-inflammatory effects, anti-androgenic effects (mediated via androgen-receptor blockade), antiestrogenic effects, growth factor inhibition, and others.” Popular belief, however, centers on the action of saw palmetto as an inhibitor of the conversion of testosterone (T) to dihydrotestosterone (dihydrotestosterone) by the enzyme, 5 a-reductase. There have been a variety of in vitro studies performed with Permixon using human skin fibroblasts, primary cultures of human benign prostatic hyperplasia, and other models.”’ These studies have generally demonstrated inhibition of type 1 and type 2 5 a-reductase activity, leading to a decrease in dihydrotestosterone production. In many cases, these studies have used supraphysiologic doses of Permixon, which raises concern regarding the true clinical effect of this agent.

TABLE. Plant Extracts Available for the Treatment of Benign Prostatic Hyperplasia

Saw palmetto (Serenoa repens)
African plum (Pygeum africanum)
β-sitosterol (Harzol)
Pollen extract (Cernilton)
Stinging nettles
South African star grass (Hypoxis rooperi)

TABLE. Suggested Mechanisms of Action of Phytotherapeutic Agents Used to Treat Benign Prostatic Hyperplasia

Inhibition of 5 a-reductase
Anti-inflammatory effects
Antiandrogenic effects (via androgen-receptor blockage)
Antiestrogenic effects
Growth factor inhibition
Protection or improvement in bladder (detrusor) function
Effects on cholesterol metabolism
Reduction in sex hormone-binding globulin

Clinical studies in humans have included a 3-month trial in 33 men awaiting suprapubic prostatectomy. These patients were randomized to receive finasteride, flutamide, placebo, or Permixon for 2 to 3 months prior to surgery. Following removal of the prostate, T, dihydrotestosterone, and growth factor levels were measured in the removed tissue. In the control group, regional distribution of all three measured factors was highest in the periurethral area and lowest in the subcapsular zone. After treatment with Permixon or finasteride, dihydrotestosterone and growth factor levels decreased significantly, with no difference in the intraprostatic distribution as was seen in those patients receiving placebo. In men treated with flutamide, there was no change in T or dihydrotestosterone levels although growth factor levels decreased throughout the prostate. The authors concluded that both finasteride and Permixon led to important changes in androgen support, primarily within the periurethral zone of the prostate. Rhodes et al. have also compared the effects of finasteride and Permixon using in vivo and in vitro studies. In rats stimulated with T or dihydrotestosterone, finasteride inhibited prostate growth while there was no change with Permixon. In a 7-day trial in 32 healthy male volunteers, finasteride led to decreased dihydrotestosterone levels while no significant change was seen in those men receiving Permixon. Strauch et al. have also demonstrated that Permixon does not lead to any significant change in serum dihydrotestosterone levels in men treated with this agent. Further evidence against clinically relevant 5 a-reductase activity associated with saw palmetto includes a lack of effect on serum prostate-specific antigen levels noted in several studies, and a minimal reduction in prostate size seen among men treated with Permixon for 6 months in one large clinical trial in Europe.

In vitro studies have also suggested alternative mechanisms of action associated with saw palmetto. Using human foreskin fibroblasts, Sultan et al. found that this agent inhibits receptor binding of androgens. As has been noted for 5 a-reductase inhibition, evidence of clinically significant antiandrogenic activity has not been presented to date. Studies using Permixon have also suggested possible antiestrogenic effects. In a placebo-controlled trial in 35 men with benign prostatic hyperplasia who underwent surgery after treatment for 3 months, a significant decrease in estrogen receptor activity was noted in the Permixon-treated patients compared to those receiving placebo. The authors concluded that this antiestrogenic effect was likely mediated by competitive blocking of the translocation of cystosolic estrogen receptors to the nucleus, which may lead to inhibition of estrogen-mediated prostatic growth. Finally, German investigators have found evidence that saw palmetto has anti-inflammatory effects in patients with benign prostatic hyperplasia. Among a small group of men who subsequently underwent open prostatectomy, those receiving saw palmetto showed a significant reduction in periglandular stromal edema, intraglandular congestion, and congestive prostatitis compared to controls.

Clinical Studies

In the mid-1980s, several placebo-controlled clinical trials were performed in Europe with saw palmetto in men with symptomatic benign prostatic hyperplasia. Champault et al. studied 110 men and reported a significant improvement in dysuria and nocturia in patients treated with saw palmetto compared to those receiving placebo. The mean urinary flow rate increased significantly in the saw palmetto group and was unchanged among the controls. Limitations of this study included the short duration of only 1 month and the absence of standardized assessment of subjective symptoms since validated instruments such as the American Urological Association (AUA) symptom score were not then available. Smith et al. performed a similar controlled trial using saw palmetto in 80 men with voiding symptoms and benign prostatic hyperplasia. Although an improvement in the subjective assessment of symptoms and urinary flow rate were seen in both the placebo group and among those men treated with saw palmetto, there was no significant difference between the results of treatment in either group. In general, the early trials concerning saw palmetto are limited by small numbers of patients and brief, one- to two-month treatment intervals.

More recent, larger scale clinical trials using saw palmetto in men with lower urinary tract symptoms have also been reported. In an open-label study conducted in Belgium, 505 men with mild to moderate symptoms were treated with saw palmetto for 3 months. The mean peak flow rate improved from 9.8 mL per second to 12.2 mL per second, and the mean AUA symptom score decreased from 19.0 to 12.4. Overall, 88% of patients and physicians considered the therapy to be effective for relieving urinary symptoms. There was also a small but statistically significant decrease in prostate volume assessed by transrectal ultrasound, of 9.2% noted in men treated with saw palmetto. While saw palmetto appeared to lead to subjective and objective improvement in men with benign prostatic hyperplasia, the lack of placebo controls in this trial limits drawing conclusions from it. In a 6-month open-label study conducted at the University of Chicago that incorporated urodynamic evaluation of patients treated with saw palmetto, the current author and colleagues found that the mean AUA symptom score improved from 19.5 to 12.3 (p < .001). No improvements in urodynamic parameters such as peak flow rate, detrusor pressure, or postvoid residual were demonstrated, however. Men receiving saw palmetto reported no adverse effects, and there were no changes in routine serum chemistries or prostate-specific antigen levels noted. Finally, in a meta-analysis of 2794 men treated with Permixon, information on changes in peak urinary flow rate and nocturia were available and compared to placebo groups. Based on this analysis, the estimated effect of Permixon on peak flow rate beyond the placebo effect is 1.87 mL per second, and frequency of nocturia is decreased by a mean of 0.55 over placebo.

In the largest randomized trial concerning saw palmetto reported to date, 1098 men with moderate symptoms received Permixon or finasteride for 6 months. The study was conducted at 87 centers in Europe and did not include a placebo control group. There was a significant improvement in the mean symptom score from 15.7 to approximately 9.5 noted in both groups. While both groups demonstrated a significant increase in the mean peak urinary flow rate, the improvement was statistically better in those men treated with finasteride. There were few adverse effects noted in either group although there was less evidence of sexual dysfunction among the men receiving Permixon. Prostate volume was measured by transrectal ultrasound and showed a significant decline in both groups. Patients treated with finasteride, however, had an 18% decrease compared to only 6% in those treated with Permixon (p < .001). In addition, there was a 41% decrease in serum prostate-specific antigen levels and a 3% increase in those patients treated with finasteride and Permixon, respectively. These findings appear to indicate that saw palmetto leads to no or minimal clinically relevant 5 a-reductase inhibition. In a separate analysis of these results, the investigators demonstrated that the response to finasteride and Permixon was independent of pretreatment prostate size.

The results of the Veterans Administration (VA) Cooperative Trial in the United States, in which men were randomized to receive finasteride, terazosin, both drugs, or placebo, must be taken into account when assessing the results of this large European trial of Permixon versus finasteride. Since the findings of the VA trial suggested that finasteride was no more effective than placebo, it is possible that the results of the European study may largely indicate a placebo effect in patients receiving Permixon as well as in those treated with finasteride.

Summary

Saw palmetto is a well-tolerated plant extract that appears to lead to few, if any, significant adverse effects. While much attention has focused on the action of saw palmetto as a 5 a-reductase inhibitor, there is little evidence to suggest that it has a significant, clinically relevant effect on prostate size or serum prostate-specific antigen levels. Therefore, it seems unlikely that saw palmetto can be considered to have a similar efficacy as finasteride. Alternative proposed mechanisms of action may play a role in improving urinary symptoms although further study is necessary concerning possible effects on prostatic inflammation, edema, and others. Overall, while a number of clinical trials have suggested that saw palmetto leads to significant improvement in voiding symptoms and urodynamic measures of obstruction, there is a need for properly conducted, placebo-controlled trials to determine whether this agent is truly effective in treating men with benign prostatic hyperplasia.

Pygeum africanum

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June 21, 2011 at 9:46 am

The African plum tree, Pygeum africanum, is the source of another popular phytotherapeutic agent. The medicinal portion of the plant comes from the deeply fissured bark, which has been used by natives of southern Africa for many centuries. The primary components of Pygeum that are felt to be active in alleviating voiding symptoms secondary to benign prostatic hyperplasia are phytosterols, linear alcohols, and triterpenoids. In vitro studies have demonstrated that Pygeum is a potent inhibitor of prostatic fibroblast proliferation in response to direct activators of protein kinase C and to a variety of growth factors. These actions are felt to lead to anti-inflammatory effects within the prostate. Also, it appears that phytosterols have an inhibitory effect on the production of prostaglandin E2 and F2 alpha, which may help relieve vascular congestion and local hyperemia.

Although most research concerning Pygeum has focused on anti-inflammatory actions, the salutary effects of this agent may also be attributed to effects on the detrusor. Using Tadenan, an extract of Pygeum marketed by a French pharmaceutical company, Levin and his colleagues have conducted a series of investigations on bladder physiology. The initial response of the detrusor muscle to bladder outlet obstruction is smooth muscle hypertrophy and an increase in bladder mass. These changes in the detrusor may lead to reduced bladder capacity, hypercon-tractility, and other effects leading to a variety of voiding symptoms. In rabbits, the experimental creation of partial bladder outlet obstruction rapidly results in urothelial hyperplasia, smooth muscle hypertrophy, and increased collagen synthesis and deposition within the bladder. These changes lead to a decrease in the contractile response of the detrusor to stimulation and biochemical evidence of bladder dysfunction, with a reduction in the activities of citrate synthase and calcium ATPase.

Among the first responses to bladder outlet obstruction is fibroblast hyperplasia induced by an increase in basic fibroblast growth factor activity. It has been demonstrated that Tadenan inhibits fibroblast hyperproliferaton caused by growth factors, giving rise to the suggestion that this plant extract may improve bladder function in patients with prostatic obstruction. In their initial study, Levin et al. randomized rabbits to receive Tadenan at various doses for 3 weeks or to a control group. Partial bladder outlet obstruction was then experimentally created to simulate the effects of benign prostatic hyperplasia; the animals were sacrificed 2 weeks later. Pretreatment with Tadenan led to a significant protective effect on the contractile response of the detrusor to a variety of forms of stimulation while having no measurable effect on the overall increase in bladder mass. Subsequently, these same investigators reported that pretreatment of rabbits with Tadenan had a beneficial effect on metabolic dysfunction seen in the partially obstructed bladder. While both control and treated animals had an initial decrease in citrate synthase and calcium ATPase levels, only those rabbits receiving Tadenan had a return of both enzymes to near normal levels within 7 to 14 days after the obstruction was created. The clinical relevance of these effects is unclear, however, since the dosages utilized in the study were well above physiologic levels. In addition, pretreatment of patients prior to the development of bladder outlet obstruction is rarely feasible. Therefore, it is unclear what effect Tadenan might have on detrusor function and physiology if administered after a prolonged period of obstruction, as typically occurs in patients with benign prostatic hyperplasia.

Clinical Studies

There has been only limited study of the effectiveness of Pygeum in men with symptomatic benign prostatic hyperplasia. Similar to the situation with other phytotherapeutic agents, most of these studies involved short treatment intervals and lacked standard means of assessing therapeutic outcome. In a placebo-controlled French study of 120 men treated for 6 weeks, patients receiving Pygeum had a significant improvement in symptoms of nocturia, hesitancy, and sense of incomplete bladder emptying compared to controls. Barlet et al. studied 263 patients treated with Pygeum or placebo for 2 months and found that the percentage of patients with symptomatic improvement was significantly greater among those men receiving Pygeum (66% versus 31%). Overall, the efficacy of Pygeum in men with benign prostatic hyperplasia remains unproven and further study of this agent is required.

Phytosterols

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June 21, 2011 at 9:45 am

Phytosterols are a class of compounds that have been suggested to be the most important component of several phytotherapeutic products used for treating benign prostatic hyperplasia. Phytosterols are derived from a number of plants, including Hypoxis rooperi (South African star grass). There have been a variety of mechanisms proposed by which  phytosterols may improve voiding symptoms, including 5 a-reductase inhibition, anti-inflammatory effects, antiandrogenic actions, growth factor inhibition, antiestrogenic effects, and others. Beta-sitosterol has been suggested to be the most important phytosterol in treating voiding symptoms secondary to benign prostatic hyperplasia.

Harzol is a prescribable phytotherapeutic product manufactured in Germany. This agent is composed of a mixture of phytosterols that include primarily beta-sitosterol as well as smaller amounts of campesterol, stigmasterol, and other compounds. Although it has been suggested that beta-sitosterol is the most important active component of Harzol, it is not known which compounds are responsible for its effect on men with benign prostatic hyperplasia. Following initial study suggesting an improvement in urinary symptoms and flow rates in patients with benign prostatic hyperplasia treated with Harzol, Berges et al. published the results of a randomized, multicenter, placebo-controlled trial. In this study, 200 men with symptomatic benign prostatic hyperplasia were treated with Harzol or placebo three times per day for 6 months. Among men receiving Harzol, the International Prostate Symptom Score (IPSS) improved from a mean of 14.9 to 7.5 while those treated with placebo showed a mean symptom score improvement from 15.1 to 12.8 (p < .01). Similarly, mean peak urinary flow rate increased from 9.9 to 15.2 cc per second in the Harzol group, compared to 10.2 to 11.4 cc per second among controls (p < .01). There was also a significant decrease in postvoid residual urine volume seen in men treated with Harzol compared to controls. No severe adverse effects were noted secondary to Harzol, and there was no significant change in prostate volume.

Other studies concerning the use of phytosterol preparations composed primarily of beta-sitosterol have also been presented. Klippel et al. randomized 177 men with benign prostatic hyperplasia to receive Azuprostat, a phytosterol preparation marketed in Europe, or placebo for 6 months. In results presented at the 4th International Consultation on benign prostatic hyperplasia in 1997, there was a significant difference in IPSS improvement between men receiving Azuprostat and those receiving placebo (5.4 points, p < .01). In addition, the difference in peak urinary flow rate improvement (4.5 cc per second) and reduction in postvoid residual volume (33.5 cc) also indicated a significantly better response to the plant extract than to placebo.

Pollen Extract

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June 21, 2011 at 9:44 am

Studies have suggested that a number of phytotherapeutic products derived from the pollen extract of a variety of plants are of value in treating men with benign prostatic hyperplasia. Most of these studies have used Cernilton, a pharmaceutical product composed of the pollen extract from several plants grown in Sweden. The two principal active constituents of Cernilton are a water soluble fraction and an acetone soluble fraction containing three betasterols. Animal studies using Cernilton have demonstrated a significant decrease in the size of the prostate associated with epithelial cell atrophy, a decline in total and prostatic acid phosphatase levels, and an increase in zinc concentrations within the prostate. In addition, the water soluble fraction of Cernilton has been shown to inhibit the immortal human cell line growth in culture derived from prostate carcinoma. Finally, it has been shown that the hormone-stimulated growth of benign prostatic hyperplasia tissue transplanted into nude mice is significantly inhibited by Cernilton extract.

Clinical studies with Cernilton have included a double-blind, randomized trial in which 60 men awaiting surgery for benign prostatic hyperplasia were randomized to receive Cernilton or placebo for 6 months. No adverse effects or changes in hematologic parameters were seen in patients treated with this plant extract. Based on a modified Boyarsky symptom score, men treated with Cernilton showed statistically significant improvement in subjective symptoms compared to men in the control group (69% versus 29%, respectively, p < .009). When analyzed by individual voiding symptoms, only nocturia and a sense of incomplete emptying significantly improved in the men treated with Cernilton compared to those receiving placebo. Although no change in peak urinary flow rate or voided volume was noted in either group of patients, residual urine volume declined significantly in those men treated with Cernilton (mean 145 cc to 102 cc after 6 months) compared to controls (p = .025). Finally, based on transrectal ultrasound measurements performed prior to treatment and after 6 months, a small but statistically significant decrease in prostate size in patients receiving Cernilton was noted compared to those in the placebo group (p = .025).

The use of Cernilton has also been studied in men with chronic prostatitis and prostatodynia. In a non-randomized, open-label investigation, 90 men who had had symptoms for 1 year or more and had no evidence of bacterial infection received the pollen extract for 6 months. Subjective assessment of perineal pain, frequency, and dysuria were assessed as well as the results of digital rectal examination, white blood cell counts in expressed prostatic secretions, complement levels in the seminal fluid, and uroflowmetry. There was a favorable response seen in 78% (56 of 72) of those without complicating factors such as urethral strictures or bladder neck contracture, and complete resolution of all symptoms and signs of prostatitis was noted in 36% (26 of 72). Results were poor in those with complicating factors, with only 1 of 18 (6%) showing any significant improvement in subjective or objective outcome measures. Although these results suggest that there may be a role for Cernilton in men with nonbacterial prostatitis and pelvic pain syndromes, the lack of placebo controls in this study makes it difficult to draw conclusions regarding the efficacy of this agent.

Finally, the results of a study comparing Cernilton with the Pygeum extract Tadenan in men with symptomatic benign prostatic hyperplasia have been reported. Superior improvements in voiding symptoms, urine flow rate, and postvoid residual volume were noted among men treated with Cernilton.